Poly aromatic sodium channel blockers

Abstract

Polyaromatic sodium channel blockers represented by the formula: are provided where the structural variables are defined herein. The invention also includes a variety of compositions, combinations and methods of treatment using these inventive sodium channel blockers.

1 - 47 . (canceled) 
     
     
         48 . A method of treating chronic bronchitis, bronchiectasis, cystic fibrosis, sinusitis, ventilator-induced pneumonia, asthma, chronic obstructive pulmonary disease, emphysema, pneumonia or rhinosinusitis, comprising administering to a human in need thereof an effective amount of a compound represented by the formula (I): 
       
         
           
           
               
               
           
         
       
       and racemates, enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts, thereof, wherein:
 X is hydrogen, halogen or lower alkyl; 
 Y is hydrogen or —N(R 2 ) 2 ; 
 R 1  is hydrogen or lower alkyl; 
 each R 2  is, independently, —R 7 , —(CH 2 ) m —OR 8 , —(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —(CH 2 ) n —(Z) g —R 7 , —(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , or 
 
       
         
           
           
               
               
           
         
         R 3  and R 4  are each, independently, hydrogen, lower alkyl, hydroxyl-lower alkyl, phenyl, (phenyl)-lower alkyl, (halophenyl)-lower alkyl, ((lower-alkyl)phenyl)-lower-alkyl, ((lower-alkoxy)phenyl)-lower-alkyl, (naphthyl)-lower-alkyl, or (pyridyl)-lower-alkyl, or a group represented by formula A or formula B, with the proviso that at least one of R 3  and R 4  is a group represented by the formula A or formula B;
   —(C(R L ) 2 ) o - x -(C(R L ) 2 ) p A 1   formula A:
 
 
         A 1  is a C 7 -C 15 -membered aromatic carbocycle substituted with at least one R 5  and the remaining substituents are R 6 ; 
         each R L  is, independently, —R 7 , —(CH 2 ) n —OR 8 , —O—(CH 2 ) m —OR 8 , —(CH 2 ) n —NR 7 R 10 , —O—(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —O—(CH 2 CH 2 O) m —R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —O—(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —O—(CH 2 ) m —C(═O)NR 7 R 10 , —(CH 2 ) n —(Z) g —R 7 , —O—(CH 2 ) m —(Z) g —R 7 , —(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , —O—(CH 2 ) m —CO 2 R 7 , —OSO 3 H, —O-glucuronide, —O-glucose, 
       
       
         
           
           
               
               
           
         
         each o is, independently, an integer from 0 to 10; 
         each p is, independently, an integer from 0 to 10; 
         with the proviso that the sum of o and p in each contiguous chain is 
         from 1 to 10; 
         each x is, independently, O, NR 10 , C(═O), CHOH, C(═N—R 10 , CHNR 7 R 10 , or a single bond; 
         each R 5  is, independently, Link-(CH 2 ) n —CAP, Link-(CH 2 ) n —(Z) g —CAP, Link-(CH 2 )(Z) g —(CH 2 ) m —CAP, —(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8  or —O—(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 ; 
         each R 6  is, independently, R 5 , —R 7 , —OR 11 , —N(R 7 ) 2 , —(CH 2 ) m —OR 8 , —O—(CH 2 ) m —OR 8 , —(CH 2 ) n —NR 7 R 10 , —O—(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —O—(CH 2 CH 2 O) m —R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —O—(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —O—(CH 2 ) m —C(═O)NR 7 R 10 , —(CH 2 ) n —(Z) g —R 7 , —O—(CH 2 ) m —(Z) g —R 7 , —(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , —O—(CH 2 ) m —CO 2 R 7 , —OSO 3 H, —O-glucuronide, —O-glucose, 
       
       
         
           
           
               
               
           
         
         wherein when two R 6  are —OR 11  and are located adjacent to each other on the aromatic carbocycle or aromatic heterocycle, the two OR 11  may form a methylenedioxy group; 
         each R 7  is, independently, hydrogen, lower alkyl, phenyl or substituted phenyl; 
         each R 8  is, independently, hydrogen, lower alkyl, —C(═O)—R 11 , glucuronide, 2-tetrahydropyranyl, or 
       
       
         
           
           
               
               
           
         
         each R 9  is, independently, —CO 2 R 7 , —CON(R 7 ) 2 , —SO 2 CH 3 , —C(═O)R 7 , —CO 2 R 13 , —CON(R 13 ) 2 , —SO 2 CH 2 R 13 , or —C(═O)R 13 ; 
         each R 10  is, independently, —H, —SO 2 CH 3 , —CO 2 R 7 , —C(═O)NR 7 R 9 , —C(═O)R 7 , or —CH 2 —(CHOH) n —CH 2 OH; 
         each Z is, independently, —(CHOH)—, —C(═O)—, —(CHNR 7 R 10 )—, —(C═NR 10 )—, —NR 10 —, —(CH 2 ) n —, —(CHNR 13 R 13 )—, —(C═NR 13 )—, or —NR 13 —; 
         each R 11  is, independently, hydrogen, lower alkyl, phenyl lower alkyl or substituted phenyl lower alkyl; 
         each R 12  is, independently, —SO 2 CH 3 , —CO 2 R 7 , —C(═O)NR 7 R 9 , —C(═O)R 7 , —CH 2 (CHOH) n —CH 2 OH, —CO 2 R 13 , —C(═O)NR 13 R 13 , or —C(═O)R 13 ; 
         each R 13  is, independently, R 7 , R 19 , —(CH 2 ) m —NR 7 R 10 , —(CH 2 ) m —NR 7 R 7 , —(CH 2 ) m —NR 11 R 11 , —(CH 2 ) m —(NR 11 R 11 R 11 ) + , —(CH 2 ) m —(CHOR 8 ) m —(CH 2 ) m NR 11 R 11 , —(CH 2 ) m —(CHOR 8 ) m   13  (CH 2 ) m NR 7 R 10 , —(CH 2 ) m —NR 10 R 10 , —(CH 2 ) m —(CHOR 8 ) m —(CH 2 ) m —(NR 11 R 11 R 11 ) + , —(CH 2 ) m —(CHOR 8 ) m (CH 2 ) m NR 7 R 7 , 
       
       
         
           
           
               
               
           
         
         with the proviso that in the moiety —NR 13 R 13 , the two R 13  along with the nitrogen to which they are attached may, optionally, form a ring selected from: 
       
       
         
           
           
               
               
           
         
         each V is, independently, —(CH 2 ) m —NR 7 R 10 , —(CH 2 ) m —NR 7 R 7 , —(CH 2 ) m   13  (NR 11 R 11 R 11 ) + , —(CH 2 ) n —(CHOR 8 ) m —(CH 2 ) m NR 7 R 10 , —(CH 2 ) n —NR 10 R 10  —(CH 2 ) n —(CHOR 8 ) m —(CH 2 ) m NR 7 R 7 , —(CH 2 ) n —(CHOR 8 ) m —(CH 2 ) m —(NR 11 R 11 R 11 ) +  with the proviso that when V is attached directly to a nitrogen atom, then V can also be, independently, R 7 , R 10 , or (R 11 ) 2 ; 
         each R 14  is, independently, H, R 12 , —(CH 2 ) n —SO 2 CH 3 , —(CH 2 ) n —CO 2 R 13 , —(CH 2 ) n —C(═O)NR 13 R 13 , —(CH 2 ) n —C(═O)R 13 , —(CH 2 ) n —(CHOH) n —CH 2 OH, —NH—(CH 2 ) n —SO 2 CH 3 , NH—(CH 2 ) n —C(═O)R 11 , NH—C(═O)—NH—C(═O)R 11 , —C(═O)NR 13 R 13 , —OR 11 , —NH—(CH 2 ) n —R 10 , —Br, —Cl, —F, —I, SO 2 NHR 11 , —NHR 13 , —NH—C(═O)—NR 13 R 13 , —(CH 2 ) n —NHR 13 , or —NH—(CH 2 ) n —C(═O)—R 13 ; 
         each g is, independently, an integer from 1 to 6; 
         each m is, independently, an integer from 1 to 7; 
         each n is, independently, an integer from 0 to 7; 
         each -Het- is, independently, —N(R 7 )—, —N(R 10 )—, —S—, —SO—, —SO 2 —, —O—, —SO 2 NH—, —NHSO 2 —, —NR 7 CO—, —CONR 7 —, —N(R 13 )—, —SO 2 NR 13 —, —NR 13 CO—, or —CONR 13 —; 
         each Link is, independently, —O—, —(CH 2 ) n —, —O(CH 2 ) m —, —NR 13 —C(═O)—NR 13 —, —NR 13 —C(═O)—(CH 2 ) m —, —C(═O)NR 13 —(CH 2 ) m —, —(CH 2 ) n —(Z) g —(CH 2 ) n —, —S—, —SO—, —SO 2 —, —SO 2 NR 7 —, or —SO 2 NR 10 —; 
         each CAP is, independently, thiazolidinedione, oxazolidinedione, -heteroaryl-C(═O)N R 13 R 13 , heteroaryl-W, —CN, —O—C(═S)NR 13 R 13 , -(Z) g R 13 , —CR 10 ((Z) g R 13 )((Z) g R 13 ), —C(═O)OAr, —C(═O)NR 13 Ar, imidazoline, tetrazole, tetrazole amide, —SO 2 NHR 13 , —SO 2 NH—C(R 13 R 13 )—(Z) g —R 13 , a cyclic sugar or oligosaccharide, a cyclic amino sugar, oligosaccharide, —CR 10 (—(CH 2 ) m —R 9 )(—(CH 2 ) m —R 9 ), —N(—(CH 2 ) m —R 9 )(—(CH 2 ) m —R 9 ), —NR 13 (—(CH 2 ) m —CO 2 R 13 ), 
       
       
         
           
           
               
               
           
         
         wherein CAP is not hydrogen or lower alkyl; 
         each Ar is, independently, phenyl, substituted phenyl, wherein the substituents of the substituted phenyl are 1-3 substituents independently selected from the group consisting of OH, OCH 3 , NR 13 R 13 , Cl, F, and CH 3 , or heteroaryl; and 
         each W is, independently, thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)N R 13 R 13 , —CN, —O—C(═S)NR 13 R 13 , —(Z) g R 13 , —CR 10 ((Z) g R 13 )((Z) g R 13 ), —C(═O)OAr, —C(═O)N R 13 Ar, imidazoline, tetrazole, tetrazole amide, —SO 2 NHR 13 , —SO 2 NH—C(R 13 R 13 )—(Z) g —R 13 , a cyclic sugar or oligosaccharide, a cyclic amino sugar, oligosaccharide, 
       
       
         
           
           
               
               
           
         
         with the proviso that when any —CHOR 8 — or —CH 2 OR 8  groups are located 1,2- or 1,3- with respect to each other, the R 8  groups may, optionally, be taken together to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane. 
       
     
     
         49 . The method of  claim 48 , wherein the compound is represented by the formula: 
       
         
           
           
               
               
           
         
         and racemates, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts, thereof. 
       
     
     
         50 . The method of  claim 48 , wherein A 1  is selected from indenyl, napthalenyl, 1,2-dihydronapthalenyl, 1,2,3,4-tetrahydronapthalenyl, anthracenyl, fluorenyl, phenanthrenyl, azulenyl, cyclohepta-1,3,5-trienyl or 5H-dibenzo[a,d]cycloheptenyl, substituted with at least one R 5  and the remaining substituents are R 6 . 
     
     
         51 . The method of  claim 48 , wherein R 3  is hydrogen and R 4  is a group represented by formula A. 
     
     
         52 . The method of  claim 48 , wherein R 3  is hydrogen and A 1  is a group represented by the formula: 
       
         
           
           
               
               
           
         
         wherein each Q is, independently, C—H, C—R 5 , C—R 6 , or a nitrogen atom, with the proviso that at least one Q is C—R 5 . 
       
     
     
         53 . The method of  claim 52 , wherein one Q is C—R 5  and the remaining Q are C—H. 
     
     
         54 . The method of  claim 48 , wherein R 3  is hydrogen and A 1  is a group represented by the formula: 
       
         
           
           
               
               
           
         
       
     
     
         55 . The method of  claim 48 , wherein R 5  is Link-(CH 2 ) n —CAP. 
     
     
         56 . The method of  claim 48 , wherein R 5  is Link-(CH 2 ) n —(Z) g —CAP. 
     
     
         57 . The method of  claim 48 , wherein R 5  is Link-(CH 2 )(Z) g —(CH 2 ) m —CAP. 
     
     
         58 . The method of  claim 48 , wherein R 5  is —(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 . 
     
     
         59 . The method of  claim 48 , wherein R 5  is —O—(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 . 
     
     
         60 . The method of  claim 48 , wherein CAP is —(Z g )R 13 . 
     
     
         61 . The method of  claim 48 , wherein CAP is —CR 10 ((Z) g R 13 )((Z) g R 13 ). 
     
     
         62 . The method of  claim 48 , wherein the compound of formula (I) is an acid addition salt of an acid selected from the consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalensulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, and lactic acid. 
     
     
         63 . The method of  claim 48 , wherein
 X, Y, R 1 , R 2  and R 3  are each hydrogen;   R 4  is represented by formula A,   A 1  is a naphthalenyl or 1,2,3,4-tetrahydronaphthalenyl group, which is substituted by one R 5  group and the remaining substituents are hydrogen;   each R L  group is hydrogen;   x is a single bond; and   the sum of 0 and p is from 2 to 6.   
     
     
         64 . The method of  claim 63 , wherein A 1  is a naphthalenyl group which is substituted by one R 5  group and the remaining substituents are hydrogen. 
     
     
         65 . The method of  claim 63 , wherein R 5  is Link-(CH 2 ) n —CAP. 
     
     
         66 . The method of  claim 63 , wherein R 5  is Link-(CH 2 ) n —(Z) g —CAP. 
     
     
         67 . The method of  claim 63 , wherein R 5  is Link-(CH 2 )(Z) g —(CH 2 ) in —CAP. 
     
     
         68 . The method of  claim 63 , wherein R 5  is —(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 . 
     
     
         69 . The method of  claim 63 , wherein R 5  is —O—(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 . 
     
     
         70 . The method of  claim 63 , wherein CAP is —(Z g )R 13 . 
     
     
         71 . The method of  claim 63 , wherein CAP is —CR 10 ((Z) g R 13 )((Z) g R 13 ). 
     
     
         72 . The compound of  claim 48 , wherein
 X, Y, R 1  R 2  and R 3  are each hydrogen;   each R L  group is hydrogen;   x is a single bond; and   the sum of 0 and p is from 2 to 6.   
     
     
         73 . The method of  claim 72 , wherein R 5  is Link-(CH 2 ) n —CAP. 
     
     
         74 . The method of  claim 72 , wherein R 5  is Link-(CH 2 ) n —(Z) g —CAP. 
     
     
         75 . The method of  claim 72 , wherein R 5  is Link-(CH 2 )(Z) g —(CH 2 ) m —CAP. 
     
     
         76 . The method of  claim 72 , wherein R 5  is —(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 . 
     
     
         77 . The method of  claim 72 , wherein R 5  is —O—(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 . 
     
     
         78 . The method of  claim 72 , wherein CAP is —(Z g )R 13 . 
     
     
         79 . The method of  claim 72 , wherein CAP is —CR 10 ((Z) g R 13 )((Z) g R 13 ). 
     
     
         80 . The method of  claim 48 , wherein the compound of formula (I) is represented by the formula, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         81 . The method of  claim 48 , wherein the compound of formula (I) is represented by the formula: 
       
         
           
           
               
               
           
         
         Or 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         82 . The method of  claim 48 , wherein the compound of formula (I) is represented by the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.